Development of modern civilization leads to improvement of life quality and development of medical science leads to an increase in human life. On the contrary, there has been a gradual increase in generation of brain diseases, such as Parkinson's diseases, depressive disorder, schizophrenia and Alzheimer's disease; heart diseases caused by stress and a change in dietary life; and various cancers caused by the exposure of the human body to various harmful materials. Thus, there has been a need for developing an imaging diagnosis method capable of diagnosing such diseases in early stages.
Various imaging diagnosis methods have been commercialized. Particularly, a method directly applicable to clinic includes positron emission tomography (PET), which can image the in vivo distribution and biochemical variation process of a radiopharmaceutical by carrying out intravenous injection of an organic compound labeled with a radioactive isotope emitting positrons to the body. Therefore, it is possible to quantitatively determine a biochemical change in the body at the site of a lesion through such positron emission tomography, and thus to measure a degree of disease progress and to predict a degree of treatment [A. Agool, R. H. Slart, K. K. Thorp, A. W. Glaudemans, D. C. Cobben, L. B. Been, F. R. Burlage, P. H. Elsinga, R. A. Dierckx, E. Vellenga, J. L. Holter, Nucl. Med. Commun. 2011, 32, 14; N. Aide, K. Kinross, C. Cullinane, P. Roselt, K. Waldeck. O, Neels, D. Dorow, G. McArthur, R. J. Hicks, J. Nucl. Med. 2011, 51, 1559; A. Debucquoy, E. Devos, P. Vermaelen, W. Landuyt, S. De Weer, F. Van Den Heuvel, K. Haustermans, Int. J. Radiat. Biol. 2009, 85, 763.].
A radiopharmaceutical is a material administered to the human body after being labeled with a radioactive isotope to diagnose or treat diseases. The radioactive isotope used for such a radiopharmaceutical is unstable and is converted into a stable isotope while emitting radiation. The radiation emitted herein may be used for diagnosis or treatment of diseases. Radiation includes alpha-ray (α-ray), beta-ray (β-ray), gamma-ray (γ-ray), positron (β+-ray), or the like. Meanwhile, radioactive isotopes used for positron emission tomography include fluoride ([18F]F), carbon ([15C]C), nitrogen ([13N]N), oxygen ([15O]O), gallium ([68Ga]Ga), or the like. Among them, [18F] fluoride has a size similar to that of hydrogen, forms a stable bonding with a carbon atom in an organic compound, is produced with ease and shows an adequate half-life (110 minutes), and thus is reported to be very suitable for carrying out positron emission tomography [Lasne, M. C.; Perrio, C.; Rouden, J.; Bane, L.; Roeda, D.; Dolle, F.; Crouzel, C. Contrast Agents II, Topics in Current Chemistry, Springer-Verlag, Berlin, 2002, 222, 201-258; Bolton, R. J. Labeled Compd. Radiopharm. 2002, 45 485-528].
According to a method for forming [18F] fluoride, a cyclotron, which is a circular collider, is used generally to irradiate positrons to [18O]H2O [M. R. Kilbourn, J. T. Hood, M. J. Welch, Int. J. Appl. Radiat. Isot. 1984, 35, 599; G K. Mulholland, R. D. Hichwa, M. R. Kilbourn, J. Moskwa, J. Label. Compd. Radiopharm. 1989, 26, 140.]. In general, [18F] fluoride is produced in [18O]H2O solution at a significantly diluted concentration. In addition, [18O]H2O solution is very expensive and thus is recycled and reused [K.-I, Nishijima, Y. Kuge, E. Tsukamoto, K.-I. Seki, K. Ohkura, Y. Magata, A. Tanaka, K. Nagatsu, N. Tamaki. Appl. Radiat. Isot. 2002, 57, 43; D. Schoeller, Obes. Res. 1999, 7, 519; SNM Newsline, J. Nucl. Med. 1991, 32, 15N.].
In order to remove a small amount of metal impurities produced when recycling the above mentioned [18O]H2O and forming [18F] fluoride and to allow use of [18F] fluoride alone in a labeling reaction, a method for exchanging anions with a quaternary alkylammonium salt-supported polymer cartridge (Chromafixor QMA) is used generally [D. J. Schlyer, M. Bastos, A. P. Wolf, J. Nucl. Med. 1987, 28, 764; S. A. Toorongian, G. K. Mulholland, D. M. Jewett, M. A. Bachelor, M. R. Kilbourn, Nucl. Med. Biol. 1990, 17, 273; D. M. Jewett, S. A. Toorongian, G. K. Mulholland, G. L. Watkins, M. R. Kilbourn, Appl. Radiat. Isot. 1988, 39, 1109; G. K. Mulholland, R. D. T. J. Mangner, D. M. Jewett, M. R. Kilbourn, J. Label. Compd. Radiopharm. 1989, 26, 378; K. Ohsaki, Y. Endo, S. Yamazaki, M. Tomoi, R. Iwata, Appl. Radiat. Isot. 1998, 49, 373-378.].
Reaction of [18F] fluoride retained in the quaternary alkylammonium salt-supported polymer cartridge uses a metal salt, such as K2CO3, or aqueous solution containing an ammonium salt, such as TBAHCO3, dissolved therein. Due to the basicity of the salts used herein, side reactions, such as alcohol or alkene reactions, occur, thereby causing degradation of labeling efficiency undesirably. In addition, when HPLC is used to purify the resultant organofluoro-18 compound, overlap with a complex byproduct may occur to show low non-radioactivity [S. M. Okarvi, Eur. J. Nucl. Med. 2001, 28, 929; J. C. Walsh, K. M. Akhoon, N. Satyamurthy, J. R. Barrio, M. M. Phelps, S. S. Gambhir, T. Toyokuni, J. Label. Compds. Radiopharm. 1999, 42, 51; L. Lang, W. C. Eckelman, Appl. Radiat. Isot. 1994, 45, 1155; L. Lang, W. C. Eckelman, Appl. Radiat. Isot. 1997, 48, 169.].
In general, it is known that a nucleophilic substitution reaction is carried out in the presence of a polar aprotic solvent, such as acetonitrile (CH3CN), DMF and DMSO in order to increase the reactivity of a nucleophile, i.e. fluoride. However, according to a recent report, an alcohol solvent weakens the ionic bonding between a metal cation and a fluorine anion through hydrogen bonding with a fluorine metal salt to increase the nucleophilic substitution reactivity of a fluorine salt and to reduce the basicity of the bases used for [18F] fluoride labeling, thereby inhibiting the side reactions [D. W. Kim, D. S. Ahn, Y. H. Oh, S. Lee, H. S. Kil, S. J. Oh, S. J. Lee, J. S. Kim, J. S. Ryu, D. H. Moon, D. Y. Chi. J. Am. Chem. Soc. 2006, 128, 16394; S. J. Lee, S. J. Oh, D. Y. Chi, H. S. Kil, E. N. Kim, J. S. Ryu, D. H. Moon, Eur. J. Nucl. Med. Mol. Imaging. 2007, 34, 1406.].
The above-mentioned problem causes consumption of a precursor due to the base used for labeling. To solve the problem, it is possible to use a method for labeling an organic compound with [18F] fluoride by using, as a reaction solvent, a tertiary alcohol capable of reducing the basicity of the base and preventing consumption of the precursor. However, in the case of t-butanol, which is an example of such tertiary alcohols having the simplest structure, it has a low boiling point of 83° C. and thus cannot increase the reaction temperature undesirably. As another example, t-amyl alcohol has an increased boiling point of about 100° C. However, t-amyl alcohol cannot be regarded as a reaction solvent having an optimized boiling point, considering the [18F] fluoride labeling reaction temperature is 100° C. or higher.
In addition, t-amyl alcohol is not miscible with water. After the [18F] fluoride labeling reaction, the alcohol solvent should be removed, when a hydrolysis process and a purification process using high performance liquid chromatography (HPLC) or solid phase extraction (SPE) are necessary. Thus, when the solvent is not removed completely, there is a problem in that the solvent may be mixed with impurities during a purification process.
In general, the alcohol solvent used for the reaction is removed through a drying process. However, since such a process is time-consuming, there is a problem in that the actual reaction yield is decreased due to degradation of radioactivity caused by the half-life of a radioactive isotope used for labeling when the radioactive isotope has a relatively short half-life. In addition, in this case, when the radioactive isotope evaporates along with the organic solvent, a problem of environmental pollution occurs. Further, when using t-amyl alcohol frequently by using an automatic synthesis system, a part having no resistance against t-amyl alcohol during its evaporation may be damaged, resulting in a failure in preparation of a radiopharmaceutical.
Meanwhile, in order to protect workers from radioactivity during the preparation of a radiopharmaceutical, an automatic synthesis system is used in a space, so-called a hot cell, shielded with lead, and such automatic synthesis systems may be classified into non-cassette type systems (TracerLab FXFN, GE Healthcare; Modular Lab, E&Z, or the like) and cassette type systems (TracerLab MX, GE Healthcare; FastLab, GE Healthcare; AIO module, Trasis, or the like).
In the case of a non-cassette type automatic synthesis system, it is used mainly for the purpose of research and requires washing inconveniently after its use. On the other hand, a cassette type automatic synthesis system uses a disposal cassette and requires no additional washing. In addition, when exchanging a cassette, the cassette type automatic synthesis system may be used advantageously twice or more per day. First of all, the cassette type automatic synthesis system is applied to Good Manufacturing Practice (GMP) with ease. Therefore, in the case of a radiopharmaceutical requiring frequent preparation, use of a cassette type automatic synthesis system has more advantages as compared to a non-cassette type automatic synthesis system.
However, in order to allow use of such a cassette type automatic synthesis system, conditions (type of a reaction solvent, reaction temperature, reaction time, or the like) under which a radiopharmaceutical to be obtained is prepared should be adequate for a cassette. If not, a cassette may be damaged during the preparation of a radiopharmaceutical, resulting in a failure in preparation of the radiopharmaceutical.
A reaction container (see, (A) in FIG. 2) introduced to a cassette used for a cassette type automatic synthesis system includes a reagent-supplying line 11a to recover the reactants after reaction. Generally, the reagent-supplying line is designed to reach the bottom surface of the reaction container 10a in order to increase the recovery ratio (see, (A) in FIG. 2). In addition, the bottom may be formed into a round shape or V-like shape to increase the recovery ratio. Therefore, when the temperature in the reaction container 10a is increased and the solution is vaporized so that a positive pressure is applied into the reaction container 10a, the solvent causes backflow to the reagent-supplying line 11a which reaches the bottom surface. As a result, the cassette connected to the other end of the reagent-supplying line 11a is filled with the reaction solvent during the reaction time. Herein, when the cassette is made of a material having no resistance against the reaction solvent or the reaction temperature is significantly higher than the boiling point of the reaction solvent, the cassette is damaged by the pressure applied thereto, which may lead to a failure in preparation of a radiopharmaceutical. In addition, the solution flowing back to the reagent-supplying line 11a cannot participate in the reaction, and thus the whole reagents cannot participate in the reaction, resulting in a large variation in yield. This makes it difficult to ensure stability of yield. As a result, it is not possible to obtain a radiopharmaceutical adequate for GMP.
To solve the above-mentioned problems, cassettes made of a material having resistance against various solvents have been developed mostly in foreign countries. In the case of a cassette made of such a novel material, they are too expensive to be used as a disposable item. Thus, it is not cost-efficient to use such a disposable cassette in a large amount. In another method, a pinch valve is installed in the line undergoing backflow from the reactor so that the solution may not be retained in the cassette. However, such a method cannot prevent a backflow phenomenon fundamentally but merely is a temporary means for preventing the backflowing solution from being retained in the cassette.
In addition, in the case of the reaction container 10a designed in such a manner that the reagent-supplying line 11a reaches the bottom surface of the reaction container 10a (see, (A) in FIG. 2), the reagents splatter to the whole walls of the reaction container 10a due to the supply rate of the reagents, when the reagents are supplied through the reagent-supplying line 11a. Further, during the process for preparing a radiopharmaceutical labeled with F-18, a drying step is carried out to provide F-18 with reactivity after it is eluted out of the anion exchange cartridge. Herein, when nitrogen is supplied through the same line, nitrogen is supplied into the solution filled in the reaction container 10a and the supplied nitrogen causes generation of bubbles. Therefore, drying is carried out while the reagents splatter to the whole walls of the reaction container. When the solution containing a precursor is supplied back to the reaction container 10a through the reagent-supplying line 11a after drying F-18, the precursor also splatters to the wall of the reaction container 10a. Thus, participation of the reagents dried while being deposited on the walls varies each time, resulting in a variation in yield of a radiopharmaceutical. Particularly, in the case of a radiopharmaceutical sensitive to the amount of reagents, not only a variation in yield but also frequent failures in preparation thereof occur. As a result, it is difficult to accomplish stable preparation of a radiopharmaceutical.